Compositions and methods for raising blood pressure with propyl amines



United States Patent 3,495,014 COMPOSITIONS AND METHODS FOR RAISINGBLOOD PRESSURE WITH PROPYL AMINES Werner Heinrich and Walter Heigel,Ludwigshafen am Rhine, Germany, assiguors to Gebr. Giulini G.m.b.H.,Ludwigshafen am Rhine, Germany, a corporation of Germany No Drawing.Original application Nov. 19, 1963, Ser. No. 324,824, new Patent No.3,345,411, dated Oct. 3, 1967. Divided and this application Oct. 7,1964, Ser. No. 402,354

Int. Cl. A61k 27/00; C07c 85/00, 87/00 U.S. Cl. 424330 21 ClaimsABSTRACT OF THE DISCLOSURE Compositions and method of increasing bloodpressure wherein the active material is of the formula:

R is alkyl having 2 to about 8 carbon atoms, and R is hydrogen, loweralkyl, or lower cycloalkyl.

This invention relates to propylamine derivatives and provides novelcompounds of this class, new methods for production of such compounds,and methods for use of such compounds.

Said novel compounds and new methods for the production of suchcompounds are the subject of copending application Ser. No. 324,824,filed Nov. 19, 1963, now U.S. Patent 3,345,411. The instant applicationis a division of Ser. No. 324,824. Ser. No. 324,824 is acontinuation-in-part of Ser. No. 231,018, filed Oct. 16, 1962, which inturn was a continuation-in-part of Ser. No. 54,542, filed Sept, 7, 1960,now abandoned. Priority under 35 U.S.C. 119 as is noted in the oath ofthe instant application is claimed.

The novel compounds of the invention are according to the followingformula:

wherein:

(a) R is alkyl having 2 to about 8 carbon atoms; (b) R is selected fromthe group consisting of hydrogen,

lower alkyl, lower cycloalkyl.

The compounds may also be according to Formula V, infra.

Also provided by the invention, are medically acceptable salts of theabove-described compounds.

The compounds of this invention possess valuable therapeutic propertieswhich render them useful as vasopressors and in particular forincreasing blood pressure, stimulating the heart muscle, acceleratingthe heart rate and increasing cardiac output. Of outstanding importanceis that they diminish or eliminate the undesirable depressive sideeffects of morphine on respiration. A distinctive characteristic of thecompounds of the invention as vasopressor agents is that they causesubstantial blood pressure increase when administered to subjects havinglow blood pressure but do not cause such substantial blood pressureincrease when administered to subjects having normal or high bloodpressure.

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R is preferably ethyl, propyl or butyl. With respect to the salts ofthese preferred compounds, the disclosure hereinafter with reference tosalts of the vasopressor agents of the invention apply, and with respectto the amines, these preferences apply to each of the secondary andprimary derivatives.

The invention further provides the method of providing a vasopressoreffect. This is accomplished by administering a therapeutic amount of acompound according to Formula 1.

Of the compounds according to Formula I, preferred compound groups arethe following: R is ethyl, propyl, n-butyl, n-pentyl, or n-octyl, and Ris hydrogen. This pref erence applies to the primary and to thesecondary amines.

Another group of compounds within Formula I and constituting a preferredgroup of the invention, is the group wherein R is ethyl. Such compoundswherein R is cycloalkyl are particularly preferred. The salts of thesecompounds, desirably, are hydrochlorides. Specific compounds within thisgroup are: 2 ethyl-3,3-diphenylpropen-(2)-yl-amine, andcyclohexyl-[Z-ethyl 3,3 diphenyl-propen-(2)-yl]-amine. A compound to beaccorded special mention in this group is cyclohexyl-[Z-ethyl- 3,3di-phenyl-propen-(2)-yl]-amine in the form of its medicinally acceptablesalt with hydrochloric, hydrobromic or hydroiodic acid. The compounds ofthis group, from the compounds of Formula I, are of the formula:

wherein R is hydrogen, lower alkyl, or lower cycloalkyl. This groupincludes the medicinally acceptable salts of the compounds of FormulaIII.

In Formula III where R is a lower alkyl group, or a cycloalkyl group, itis of the type conventionally present as a substitutent in organic aminocompounds designed for therapeutic application, in particular, loweralkyl or cycloalkyl, and preferably contains not more than about 6carbon atoms. R can be for example, methyl, butyl, ethyl, propyl,isopropyl, isobutyl, secondary butyl, isoamyl hexyl, isohexyl,cyclohexyl and similar or related radicals.

The compounds of Formula III can be used in the form of thehydrochloride, but preferably are used as salts, e.g. acid additionsalts. The salts are crystalline solids which are soluble in water andtherefore constitute an advantageous embodiment of this invention.

The organic bases of the type shown in Formula III form salts with avariety of inorganic and organic acids conventionally used fortherapeutic application of organic amino or imino bases and includinghydrochloric, hydrobromic, hydroiodic, sulfuric, phosphoric, citric,lactic, maleic, acetic, benzoic, oxalic and related or similar acids. Inmany instances, the resulting salt crystallizes out of suitablyconcentrated solution on chilling or standing or may be precipitated byaddition of a solvent, such as ether or benzene in which the salt isinsoluble.

Another preferred group of compounds within the compounds of Formula Iis the group represented by the formula:

CeHs R1 (1V) wherein R is an alkyl group containing 2 to about 8 carbonatoms, especially 4 to about 8 carbon atoms. These compounds can be inthe form of their medicinally acceptable acid addition salts.Particularly preferred com pounds within this group are those in which Ris n-butyl, n-pentyl, or n-octyl. What is said herein with reference tosalts of Formula I, applies also to salts of Formula IV.

Included within this group of Formula IV is 2-propyl-3,3-diphenyl-propen-(2)-yl-amine. This compound has been found wellsuited to the purposes of the invention.

Another preferred group of compounds of the invention is the grouprepresented by the following formula:

in which R is alkyl, alkoxy, or halogen. These compounds can be in theform of their medicinally acceptable salts. Particular compounds of thisgroup which have been found well suited for the purposes of theinvention are the compounds wherein R is chloro, methyl or methoxy.Where R is alkyl, it is preferably a lower alkyl; Where R is alkoxy, itis preferably a lower alkoxy. What has been said herein with referenceto salts of com pounds of Formula 1, applies also to salts of compoundsof Formula IV.

Compounds according to Formula I can be produced by hydrogenatingcompounds of the formula:

wherein R is as described with reference to Formula I, to produce thecorresponding alcohol-primary amine. If a secondary amine according toFormula I is to be produced, the said alcohol-primary amine can bereacted with an alkyl or cycloakyl carbonyl compound under reducingconditions for the desired alkylation. The product propene amine canthen be obtained by dehydrating the alcohol-primary or -secondary amine,as the case may be.

The hydrogenation of the nitrile can be a catalytic hydrogenation. Adesirable catalyst for the reaction is platinum, and the reaction ispreferably carried out in a solvent for the nitrile, for example aceticacid or methanol.

The dehydration of the alcohol-amine can be carried out by the known andconventional dehydrating methods, and preferably employing asdehydrating agent gaseous hydrogen chloride with the alcohol-amine insolution. Solvents such as acetic acid can be used, and the dehydrationcan be effected by heating the solution under refiux for a timesufficient to complete the dehydration.

Where, in accordance with Formula V, halogen is present, thehydrogenation is with lithum aluminum hydride rather than catalytically.In such cases the nitrile containing chloro substituent can first bedehydrated to form an acrylonitrile derivative and this derivative canbe bydrogenated with lithium aluminum hydride to form thepropane-primary amine.

A further feature of the invention is provision of a process for theproduction of primary amines. Thus, the invention provides forproduction of primary amines such as amines of Formula I wherein R ishydrogen. The procedure involves catalytically hydrogenating thecorresponding 2-hydroxypropionitrile to form therefrom the correspondingalcohol-primary amine, and dehydrating the alcohol-primary amine to formthe product primary amine.

Where the primary amine to be produced includes halogen, as in FormulaV, the corresponding 2-hydroxypropionitrile can be dehydrated to producethe corresponding acrylonitrile, and the acrylonitrile can behydrogenated to form the primary amine.

Another feature of the invention is the provision of a process forproduction of secondary amines. Thus, there 4 can be produced compoundsaccording to Formula I wherein R is lower alkyl or lower cycloalkyl. Inthis procedure, the corresponding alcohol-primary amine, wherein thehydroxy group of the alcohol is in the 3-position, is contacted with analkyl or cycloalkyl carbonyl compound under reducing conditions toproduce the corresponding alcohol-secondary amine, and thealcohol-secondary amine is dehydrated to produce the secondary amineproduct.

Further details of preparation of compounds of the invention are set outbelow.

COMPOUNDS OF FORMULA III Compounds of this invention can be preparedutilizing the step of catalytically hydrogenating 1-ethyl-2-hydroxy-2,Z-diphenyl-propionitrile to form the corresponding2-ethyl-3-hydroxy-3,S-diphenyl-propyl-amine.

A partcularly advantageous catalyst for use in hydrogenating the nitrileis platinum. The hydrogenation reaction is preferably carried out in asolvent for the nitrile, for example acetic acid or methanol.

The 1-ethyl-2-hydroxy-2,2-diphenyl-propionitrile, which is necessary asbasic product, is obtained by condensation of benzophenone andbutyronitrile, which was proposed by Lettre.

The 2 ethyl 3,3 diphenylpropen (2) yl amine is prepared by dehydrationof the Z-ethyl-3-hydroxy-3,3-diphenylpropylamine. The dehydration iscarried out by the known and conventional dehydrating methods, and preferably there may be employed as dehydrating agent gaseous hydrogenchloride with the 2ethyl-3-hydroxy-3,3- diphenylpropylamine in solution.As solvent for the 2- ethyl-3-hydroxy-3,3-diphenylpropylamine, aceticacid can be used. The dehydration is preferably carried out by heatingthe solution under reflux for a time sufiicient to complete thedehydration.

The mono-alkylated derivatives of the hydroxylated compound are preparedby reacting the compound containing a primary amino group with an alkylor cycloalkyl carbonyl compound under reducing conditions, andpreferably the alkylation is achieved by catalytic hydrogenation of thefree base in the presence of carbonyl compounds. Thus, in accordancewith the invention, alkylating of the2-ethyl-3-hydroxy-3,3-diphenylpropylamine is carried out and thereafterthe mono-alkylated 2-ethyl-3-hydroxy-3,3-diphenyl-propylamine issubjected to dehydration to thereby obtain the mono-alkylated2-ethyl-3,3-diphenyl-propene-amine.

Alternatively, the mono-alkylated derivatives may be obtained byreacting the 2-ethyl-3-hydroxy-3,3-diphenylpropyl-amine with carbonylcompounds to form the cone sponding 1,3-oxazine and, through catalytichydrogenation, to split the 1,3-oxazine to form the amino alcohol.

Example l.-Preparation of 1-ethyl-2-hydroxy-2,2- diphenylpropionitrile54.6 g. of benzophenone and 20.7 g. of butyronitrile are dissolved in400 ml. of absolute ether. 16 g. of sodium amine powder are added andthe mixture is boiled for 7 hours at a temperature of 40 C. underreflux. Thereafter, the solution is given into 500 ml. of ice/water andstirred for 5 min. The reaction product separates at once in acrystalline form (the raw yield amounts to 66 g.=88%) which isrecrystallized by means of benzene with a loss of 20%. The melting pointthereby obtained is 162 C.

Example 2.-Preparation of 2-ethyl-3hydroxy-3,3-

diphenylpropylamine 10 g. of1-ethyl-2-hydroxy-2,2-diphenyl-propionitrile are dissolved in 200 ml. ofmethanol. 10 ml. of acetic acid are added to the mixture, and themixture is hydrogenated in the presence of platinum as catalyst. Afterthe hydrogen uptake or consumption has ceased, the reaction isinterrupted, the catalyst is filtered off and the filtrate is evaporatedin vacuo to dryness. The residue is dissolved in water, and, after theaddition of one ml. of hydrochloric acid, the solution is extracted withether. The acidified ether-phase is discarded. The aqueous phase is madealkaline with ammonia, whereby the base crystallizes out. The crystalsare recovered and crystallized from methanol. The melting point of the2-ethyl-3-hydroxy-3,3-diphenylpropylamine thereby obtained is 132 C.

Example 3.-Preparation of 2-ethyl-3,B-diphenyl-propen- (2)-ylamine-hydrochloride 5 g. of 2-ethyl-3-hydroxy-3,3-diphenylpropylamineare dissolved in 50 ml. of acetic acid. Gaseous hydrogen chloride ispassed through the solution for minutes, and thereafter the solution isboiled for one hour under reflux. The solution is then distilled todryness. The residue is dissolved in water and the acidified solutionextracted with ether. The aqueous phase is separated, made alkaline withammonia and extracted with ether. The ether phase is dried over sodiumsulfate, the ether distilled oif and the residue is dissolved inmethanolic hydrogen chloride. On the addition of absolute ether, thehydrochloride of 2-eth yl-3,3-diphenyl-aminopropen-(2)-yl iscrystallized out. The crystalline substance thereby obtained has amelting point of 232 C.

Example 4.-Cyclohexyl-[2-ethy1-3-hydroxy-3,3-diphenylpropyl] -amine 6 g.of 2-ethyl-3-hydroxy-3,3-diphenyl-propylamine are dissolved in 200 ml.of methanol. 10 ml. of freshly distilled cyclohexanone are added to thesolution and the solution is hydrogenated in the presence of a platinumcatalyst. The hydrogen consumption takes place very quickly. Thecatalyst is filtered OE and the filtrate concentrated to dryness. Theresidue is taken up in dilute hydrochloric acid and extracted withether. The hydrochloride salt which is partially recovered from theether phase, is crystallized out from methanol ether. The crystalsthereby obtained have a melting point of ISO-182 C. The water phase ismade alkaline with ammonia and thereafter extracted with ether. Afterdrying over sodium sulfate, the ether extract is subjected todistillation. The residue thereby obtained recrystallized from a mixtureof acetone and water in the ratio of 2:1. The base thus recovered has amelting point of 78-80 C.

Example 5 .-Cyclohexyl-[2-ethyl-3,3-diphenyl-propen- (2) -yl]-amine-hydrochloride 3.37 g. ofcyclohexyl-[2-ethyl-3-hydroxy-3,3-dipheny1- propyl]-amine are dissolvedin 50 ml. of acetic acid and gaseous hydrogen chloride is passed throughthe solution until the reaction mixture is strongly acidic. The mixtureis heated for two hours in a boiling water bath. The acetic acidsolution is thereafter distilled under vacuo to dryness. The residue isdissolved twice in 50 ml. portions of methanol, and each time thesolution is evaporated to dryness. The final residue is dissolved in asmall amount of methanol and the hydrochloride salt crystallized out byaddition of absolute ether. The crystalline substance thereby obtainedhas a melting point of 212-215 C.

Compounds having alkyl substituents on the amino group other than theinstances disclosed in the examples may be obtained by carrying out theforegoing experiments using in the alkylation reaction other alkyl orcycloalkyl carbonyl compounds, as for example methyl, cyclohexyl,pentyl, hexyl, butyl, diethyl, etc. It is furthermore possible toprepare, in lieu of hydrochlorides, corresponding salts of other acidsby contacting the base in the form of its solution with an acid, as forexample hydrobromic, hydroiodic, phosphoric, citric, oxalic, in place ofthe hydrochloric acid, until the reaction mixture is strongly acidic.The said solution may have to be concentrated somewhat forcrystallization, upon chilling,

to occur.

6 COMPOUNDS OF FORMULA 1v These compounds can be made by reactions asare disclosed above for the compounds of Formula III.

Example 6a.2-n-buty1-3-hydroxy-3,3-diphenylpropyl-amine 14 g.1-n-butyl-2-hydroxy-2,Z-diphenyl-propionitrile are dissolved in 350 ml.glacial acetic acid, 0.5 g. of platinum catalyst are added and thenhydrogenized. After completed hydrogenation, the catalyst is filteredoff, and the filtrate is evaporated in vacuum to dryness. The residue istreated with Water, treated with hydrochloric acid until the acidreaction, filtered off from the undissolved material, and extracted withether. The aqueous phase is made alkaline with ammonia solution,extracted with ether and the ether part dried via sodium sulfate. Afterdistilling ofi of the ether remains the2-n-butyl-3-hydroxy-3,3-diphenyl-propyl-amine is obtained. Meltingpoint: 84 C.

Example 6b.2-n-butyl-3,3-diphenyl-propen- 2 yl-amine-hydrochloride 17 g.2 n butyl-3-hydroxy-3,3-diphenyl-propyl-amine are dissolved in ml.glacial acetic acid. This solution is saturated with hydrogen chloridegas and subsequently heated for three hours to 100 C. The acetic acid isdistilled off in vacuum. The residue is dissolved in a little methanoland the 2-n-butyl-3,3-diphenyl-propen-(2)-ylamine-hydrochloride isprecipitated by addition of absolute ether. Melting point: 161 C.

Example 7a.2-n-pentyl-3-hydroxy-3,3-diphenylpropyl-amine Throughhydrogenation of 1-n-pentyl-2-hydroxy-2,2- diphenyl-propionitrile oneobtains the 2-n-pentyl-3-hydroxy-3,3-diphenyl-propyl-amine in analogousmanner according to Example 60. Melting point: 57 C.

Example 7b.-2-n-pentyl-3 ,3-diphenyl'propen-(2 yl-arninehydrochlorideThe solution of 9.5 g. 2-n-pentyl-3-hydroxy-3,3-diphenyl-propyl-amine in100 ml. glacial acetic acid is saturated with hydrogen chloride andsubsequently heated for three hours to 100 C. The acetic acid isdistilled olf in vacuum, and the 2 npentyl-3,3-diphenyl-propen-(2)-ylamine-hydrochloride remaining isrecrystallized from benzene. Melting point: 138-140 C.

Example 8a.2-n-octyl-3-hydroxy-3,3-diphenylpropyl-amine Throughhydrogenation of l-n-octyl-2-hydroxy-2,2-diphenyl-propionitrile oneobtains the 2-n-octyl-3-hydroxy- 3,3-diphenyl-propyl-amine in analogousmanner according to Example 6a. Melting point: 88 C.

Example 8b.-2-n-octyl-3 ,3-diphenyl-propen-(2) y-l-amine-hydrochlorideThe solution of 38.5 g. 2-n-octyl-3-hydroxy-3,3-diphenyl-propyl-amine in200 ml. glacial acetic acid is saturated with hydrogen chloride gas andsubsequently heated for three hours to 100 C. The crystals of2-n-octyl-3,3-diphenyl-propen-(2)-yl-amine-hydrochloride remainingbehind after distilling off of the acetic acid in vacuum, are washed-outwith absolute ether. Melting point: 157 C.

The comments made above with respect to the examples under Formula IIIas to substitutions in the examples, apply to the foregoing examples ofcompounds of Formula IV.

COMPOUNDS OF FORMULA V These compounds can be produced in a manneranalogous to production of compounds of Formula III, that is, throughhydrogenation of 1-ethyl-2-hydroxy-2,2-diarylpropionic nitrile andseparation of water. In the cases in which a halogen substitutionexists, hydrogenation can be by means of lithium aluminum hydride. Inall other cases,

the reduction can be effected catalytically. In these reactions, thereis formed a mixture of two cis-trans-forms.

Example 9.2-ethyl-3 -phenyl-3-(p-methyl-phenyl) propen- 2)-yl-amine-hydrochloride 13.3 g.1-ethyl-2-hydroxy-2-phenyl-2-(p-meithyl-phenyl)-propionic nitrile aredissolved in 400 ml. glacial acetic acid, 200 mg. platinum catalyst areadded and subsequently hydrogen is introduced. After completion ofhydrogen absorption, one filters off from catalyst, and the filtrate isevaporated in vacuum until dry. The residue is dissolved in water,treated with hydrochloric acid until the acid reaction, filtered offfrom the residue, and the filtrate added drop by drop into 20% soda lye.Therein the 2 ethyl-3-hydroxy-3-phenyl-3-(p-methyl-phenyl)-propyl-amineprecipitates. Melting point: 8890 C.

4.8 g. 2-ethyl-3-hydroxy-3-phenyl-3-(p-methyl-phenyl)- propyl-amine aredissolved in 50 ml. glacial acetic acid. This solution is saturated withhydrogen chloride gas and subsequently heated for 3 hours to 100 C. Theacetic acid is distilled off in vacuum. The residual crystals aredissolved in methanol and the 2-ethyl-3-phenyl-3-(pmethyl-phenyl)-propen-( 2 -yl-amine hydrochloride precipitated through addition ofabsolute ether. Melting point: 223-225 C.

Example 10 .2-ethyl-3 -phenyl-3 (p-methoxyphenyl)propen-(2)-yl-amine-sulfate Through hydrogenation of l ethyl 2 hydroxy2- phenyl 2 (p methoxy phenyl) propionic nitrile one obtains the 2 ethyl3 hydroxy 3 phenyl 3 (p methoxyphenyl) propyl amine in the mannerdescribed in Example 9. Melting point: 148 C.

Into a solution of 4.2 g. 2 ethyl 3 hydroxy 3- phenyl 3 (pmethoxyphenyl) propyl amine one introduces for 25 minutes dry hydrogenchloride gas and subsequently heats for 2 /2 hours to 100 C.;thereafter, the material distilled until dry. The residue is dissolvedin water, made alkaline with diluted soda lye, and then extracted withether. The ether part is dried with sodium sulfate, the ether distilledoff, and the thus obtained 2- ethyl 3 phenyl 3 (p methoxyphenyl) propen-(2)-yl-amine converted into its sulfate. The substance melts at 145165C.

Example 1 l .2-ethyl-3 -phenyl-3- (p-chlorophenyl) pro pen- 2-yl-amine-hydrochloride To a hot solution of 16.3 g. 1 ethyl 2 hydroxy2- phenyl 2 (p chlorophenyl) propionic nitrile in 300 ml. absolutebenzene, there is very quickly added 20 g. phosphorous-pentoxide. Thereaction mixture is boiled for 45 minutes under reflux, the benzenesolution decanted, and the residue is twice boiled-out with each 100 ml.absolute benzene. After distilling off of the benzene, there remains the1 ethyl 2 phenyl 2 (p chlorophenyl)-acrylo-nitrile in almostquantitative yield as yellowish oil.

A solution of 5.4 g. 1 ethyl 2 phenyl 2 (p-chlorophenyl) acrylo nitrilein 20 ml. absolute ether is added drop by drop within half an hour to asuspension of 0.76 g. lithium aluminum hydride in 100 ml. absolute etherunder ice-cooling and stirring, so that the temperature does not riseabove 5 C. The reaction mixture is still further stirred for half anhour and then treated, successively, with 0.8 ml. Water, 0.6 ml. 20%soda lye, and 2.8 ml. water. The yellow-colored ether solution is thendecanted from the granular precipitate, and this is then washed threetimes with 30 ml. absolute ether. The

2 ethyl 3 phenyl 3 (p chlorophenyl) propen- (2)-yl-amine present in theether solution is isolated as hydrochloride. Melting point: 208-211 C.

As noted above, with reference to compounds of Formula III, in the caseof the compounds of Formula V various acid addition salts of thecompounds can be provided.

2 PROPYL DERIVATIVE OF COMPOUNDS OF FORMULA III Through hydrogenation of1 propyl 2 hydroxy 2, 2-diphenyl-propionic-nitrile and subsequentseparation of water from the 2 propyl 3,3 diphenyl 3 hydroxypropyl amineformed, the 2 propyl 3,3 diphenylpropen (2) yl amine can be obtained.The starting material for production of the 2-propyl derivatives can beobtained in a manner analogous to the manner in which the startingmaterial for the compounds of Formula III is obtained.

Example 12.-2-propyl-3 ,3-diphenyl-propen- 2) yl-amine hydrochloride13.1 g. 1 propyl 2 hydroxy 2,2 diphenyl propionic-nitrile are dissolvedin 400 ml. glacial acetic acid, 200 mg. platinum catalyst are added, andsubsequently hydrogen is introduced. After hydrogen absorption ceases,the catalyst is filtered off, and the filtrate evaporated in vacuumuntil dry. The residue is dissolved in water, treated with hydrochloricacid until acid reaction, the residue is filtered off, and the filtrateadded drop by drop into 20% soda lye. The precipitated 2 propyl 3,3diphenyl-3-hydroxy propyl amine is recovered. Melting point: 108110 C.

4.8 g. 2 propyl 3,3 diphenyl 3 hydroxy propylamine are dissolved in 50ml. glacial acetic acid. This solution is saturated with hydrogenchloride gas and subsequently heated for 3 hours at C. The acetic acidis distilled off in vacuum. The crystals remaining behind are dissolvedin methanol and the 2 propyl 3,3- diphenyl propen (2) yl aminehydrochloride is precipitated through addition of absolute ether.Melting point: 213-215 C.

What is said above with reference to salts of the compounds of FormulaIII, applies as Well to the salts of the 2-propyl derivatives.

UTILITY DATA The compounds of the invention are substantially moreeffective than the corresponding Z-methyl derivatives. This can bedemonstrated by tests on anesthetized animals to which the 2-methylderivative and a 2-ethyl derivative have been administered. Furtherinformation on utility follows.

COMPOUNDS OF FORMULA III The following details were found byexperimenting with 2 ethyl 3,3 diphenyl propen (2) yl aminehydrochloride on animals.

(1) Acute toxicity:

DL 50, white mouse, i.v. 35.5 mg./kg.

DL 50, white mouse, p.o. 87.5 mg./ kg.

DL 50, white mouse, s.c. approx. 100 mg./kg. DL 50, white rat, p.o. 183mg./kg.

( 2) Chronic toxicity:

White rat, per 05 18.3 mg./kg. pro die, 20 animals: during a 30 daysfeeding body weight and general behavior normal. No toxic signs. Actionof erythrocytes and leucocytes within physiological limits. Macroscopicand microscopic no organic conditions.

(3) Picture of actions:

For the most part chronic convulsions with point of action on motorbrain centers; besides tonic components of convulsion (stimulativeelfect) vasomotor center, breath center, mainly centrally conducedincrease of blood pressure, central excitation.

(4) The effect on the blood pressure in cats underchloralose-urethane-anaesthesia2 0.5 mg./kg. i.v.: increase of bloodpressure of 40-60 mm.

Hg, effective for 6-8 minutes;

0.1 mg./ kg. i.v.: increase of blood pressure of 30-50 mm.

Hg, effective for about minutes;

1 mg./kg. i.v.: increase of blood pressure of 45-60 mm.

Hg, with longer efficiency;

2 mg./kg. i.v.: increase of blood pressure of 50-60 mm.

Hg, with long efficiency.

With normal or reduced initial blood pressure the hypertensive effect isstronger than with an increased initial blood pressure.

(5) Effect on the experimentally conduced circulatory collapse in cats:

(a) Circulatory collapse by Evipan-Sodium continuous infusion:

0.1-2.0 rng/kg. i.v.: strong hypertensive effect for a prolonged time(b) Circulatory collapse by Acethylcholin continuous infusion:

0.l-2.0 mg./ kg. i.v.: stronger hypertensive effect with longefficiency.

(6) Effect on the breathing in narcotized cats:

0.1-2.0 rug/kg. i.v.: strong stimulation of breathing.

(7) Effect on the heart:

(a) frog, in situ perfused according to Biilbring.

0.1 mg. percent (1:l,000,000): no change of frequency and minute volume0.4 mg. percent (1:250,000): no influence on frequency and minute volume1 mg. percent (1:l00,000): decrease of minute volume with constantfrequency.

(b) ECG in guinea-pigs:

Doses of 0.63-2.0 mg./ kg. cause no significant change in ECG apart froma temporary decrease of frequency.

(8) Stimulative effect in rabbits under urethane anaesthesia:

0.1-2.5 mg./kg. i.v.: strong stimulative effect.

(9) Effect on the breathing of rabbits under morphine:

The damaged breathing caused by an intravenous injection of 5-7 mg./ kg.morphine hydrochloride (decrease of the volume and frequency ofbreathing) is normalized by an intravenous injection of 0.1-2.5 mg./ kg.

COMPOUNDS OF FORMULA IV COMPOUNDS OF FORMULA V These compounds areespecially preferred since they have an especially pronounced effect onblood pressure and this effect is particularly longlasting.

Effects on the blood pressure of the cat under urethane chloralosenarcosis for compounds of Formula V, as follows, were noted.

2 ethyl 3 phenyl 3 (p chlorophenyl) propen- (2)-yl-amine ashydrochloride, gluconate and methanesulfonate:

1 mg./kg. i.v.: blood pressure increase of 40-50 mm.

Hg, lasting about 30-40 minutes;

10 2 mg./kg. i.v.: blood pressure increase of 60 mm. Hg,

lasting about 2-4 hours; 3 mg./kg. i.v.: blood pressure increase of60-80 mm.

Hg, lasting about 4 hours and longer.

For lower starting blood pressure the blood pressure increase effect isstronger and lasts longer than in normal or high starting bloodpressure.

1 (3 hydroxyphenyl) 1 hydroxy 2 N ethylaminoethane-hydrochloride of thestructural formula @onon-onmnona-nor 1 mg./ kg. i.v.: blood pressureincrease of about 20 mm.

Hg, lasting about 4-8 minutes;

2 mg./kg. i.v.: blood pressure increase of 20-30 mm.

Hg, lasting about 4-8 minutes;

3 mg./kg. i.v.: blood pressure increase of 40-60 mm.

Hg, lasting about 4-8 minutes;

4 rug/kg. i.v.: blood pressure increase of 40-60 mm.

Hg, lasting about 4-8 minutes.

ephedrine:

1 mg./kg. i.v.: blood pressure increase of 20-40 mm.

Hg, lasting about 30-40 minutes; 2 mg./kg. i.v.: blood pressure increaseof 40-50 mm.

Hg, lasting about 30-40 minutes; 3 mg/kg. i.v.: blood pressure increaseof 40-50 mm.

Hg, lasting about 30-40 minutes.

In all cases, the starting blood pressure was about the same and wasbetween and mm. Hg.

PROPYL DERIVATIVES OF COMPOUNDS OF FORMULA III Compounds of Formula IIIhaving a propyl group in the 2-position instead of an ethyl group, areof particular interest because of their long-lasting blood pressureeffect.

Effects as follows were noted for the blood pressure of the cat inurethane chloralose narcosis:

2-propyl-3,3-diphenyl-propen-(2)-yl-amine as hydrochloride, gluconateand methanesulfonate:

0.5 mg./kg. i.v.: blood pressure increase of 40-60 mm. Hg, lasting about30-40 minutes;

1.0 mg./kg. i.v.: blood pressure increase of 45-60 mm. Hg, lasting about2-3 hours;

mg./kg. i.v.: blood pressure increase of 70-90 mm. Hg, lasting about 3-4hours, and longer.

For lower starting blood pressure the blood pressure increasing effectis stronger and lasts longer than in the case of raised or normalstarting blood pressure.

1 (3 hydroxyphenyl) 1 hydroxy 2 N ethylaminoethane hydrochloride of thestructural formula:

1 mg./kg. i.v.: blood pressure increase of about 20 mm.

Hg, lasting about 4-8 minutes;

2 rug/kg. i.v.: blood pressure increase of 20-30 mm. Hg,

lasting about 4-8 minutes;

3 mg./ kg. i.v.: blood pressure increase of 40-60 mm. Hg,

lasting about 4-8 minutes;

4 mg./ kg. i.v.: blood pressure increase of 40-60 mm. Hg,

lasting about 4-8 minutes.

The effect of ephedrine is as reported above for compounds of Formula V.In all cases, the starting blood pressure was about the same and wasbetween 80 and 100 mm. Hg.

1 1 COMPOSITIONS The compounds in accordance with the invention may begiven in dosage form hypodermically or intramuscu larly in the form ofHCl salt, or in the form of their salts in isotonic physiologicallyacceptable solutions, as for example water saline or peanut oil.Locally, they may be used in solution as a spray and in ointment.

The exact dosage in each instance is entirely dependent on the effectsought to be achieved, the mode of adminis tration employed and thedegree of caution which must be observed. Dosage can be, for example,mg. for parenteral administration. In any instance, there is employed atleast that amount of the compound, i.e. active agent, necessary toproduce the desired physiological effect, but less than that amountproducing an undesired toxic effect.

The compounds of the invention, as can be readily appreciated, alsoconstitute valuable tools for use in medical research, as for instancein connection with animal experiments and in particular in the study oftheir effect on the blood pressure by stimulating the contraction of themuscular tissue of the capillaries and arterioles.

What is claimed is:

1. A method of raising blood pressure which comprises administering tothe subject at least a therapeutic amount of a compound of the formula:

wherein:

(a) R is alkyl having 2 to about 8 carbon atoms; (b) R is selected fromthe group consisting of hydrogen, lower alkyl and lower cycloalkyl; ormedicinally acceptable salts thereof.

2. The method of claim 1, wherein R is propyl.

3. The method of claim 1, wherein R is n-butyl.

4. The method of claim 1, wherein R is n-pentyl.

5. The method of claim 1 wherein R is n-octyl.

6. A method of raising blood pressure which comprises administering tothe subject at least a therapeutic amount of a compound of the formula:

wherein R is selected from the group consisting of hydrogen, loweralkyl, and lower cycloalkyl, or medicinally acceptable salts thereof.

7. The method of claim 6 wherein R is cycloalkyl.

8. The method of claim 6, wherein said compound is in the form of thehydrochloride.

9. The method of claim 6, wherein R is hydrogen.

10. The method of claim 6, wherein R is cyclohexyl.

11. The method of claim 6, wherein R is cyclohexyl and said compound isin the form of a medicinally acceptable salt with a member selected fromthe group consisting of hydrochloric, hydrobromic, and hydroiodic acid.

(III) 12. A method of raising blood pressure which comprisesadministering to the subject at least a therapeutic amount of a compoundof the formula:

wherein R is an alkyl radical containing 2 to about 8 carbon atoms, ormedicinally acceptable salts thereof.

13. Method of claim 12, wherein R is n-pentyl.

14. Method of claim 12, wherein R is n-butyl.

15. Method of claim 12, wherein R is n-octyl.

16. Method of claim 12, wherein said compound is in the form of thehydrochloride.

17. A method of raising blood pressure which comprises administering tothe subject at least a therapeutic amount of2-propyl-3,3-diphenyl-propen-(2)-yl-amine or medicinally acceptablesalts thereof.

18. A method of raising blood pressure which comprises administering tothe subject at least a therapeutic amount of a compound in which R isselected from the group consisting of alkyl, alkoxy and halogen, ormedicinally acceptable salts thereof.

19. Method of claim 18, wherein R is chloro, methyl, or methoxy.

20. A therapeutic agent for parenteral administration in the form of aphysiologically acceptable solution, comprising a blood pressure raisingamount of a compound of the following formula,

wherein:

(a) R is alkyl having 2 to about 8 carbon atoms; (b) R is selected fromthe group consisting of hydrogen, lower alkyl and lower cycloalkyl; or amedicinally acceptable salt thereof, dissolved in a vehicle suitable forsuch administration.

wherein:

References Cited FOREIGN PATENTS 525,752 6/1956 Canada.

ALBERT T. MEYERS, Primary Examiner STANLEY I. FRIEDMAN, AssistantExaminer

